Catalytic Asymmetric Construction of 3,3′‐Spirooxindoles Fused with Seven‐Membered Rings by Enantioselective Tandem Reactions

Abstract

The first catalytic asymmetric construction of a spirooxindole scaffold incorporated with a seven-membered benzodiazepine moiety has been established by a three-component (isatin, 1,2-phenylenediamine, cyclohexane-1,3-dione) tandem reaction catalyzed by a chiral phosphoric acid. Structurally complex spirobenzodiazepine oxindoles with one quaternary stereogenic center are obtained in high yield with excellent enantioselectivity (up to 99% yield, enantiomeric ratio>99.5:0.5). This approach takes advantage of organocatalytic asymmetric tandem reactions to efficiently construct the structurally rigid spirobenzodiazepine oxindole architecture with high enantiopurity in a single transformation, which involves a cascade enamine-imine formation/intramolecular Mannich reaction sequence.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…Again the chiral phosphoric acid derivative 728 was used as the organocatalyst to obtain 730 in excellent yields and enantioselectivities. [287] In line with theirp revious report on the synthesis of structurally complexs ubstituted indole frameworks,S hi and co-workers recently published an asymmetric domino Michael-initiatedd earomatization reactionf ollowed by nucleophilic aza-cyclization. Indol-3-ylmethanols 721 andt ryptamine derivatives 731 reacted together in the presenceo fc hiral phosphoric acid derivative 733 to generate pyrroloindoline-based indole derivatives 732 in good to excellent stereoselectivities (Scheme 195).…”

“…These authors also developed a three‐component domino Michael/Pictet–Spengler reaction between 721 , isatin derivatives 302 , and 2‐aminomalonate ( 727 ) for the synthesis of bispirooxindoles containing the tetrahydro‐β‐carboline framework 726 in excellent stereoselectivities, using the chiral phosphoric acid 728 as the catalyst (Scheme ) Another three‐component domino enamine‐imine formation/intramolecular Mannich reaction between isatin derivatives 302 , 1,2‐phenylenediamine derivatives 729 , and 5,5‐dimethylcyclohexane‐1,3‐dione ( 424a ) was employed by these authors to synthesize spirooxindole scaffolds 730 that contain a benzodiazepine moiety (Scheme ). Again the chiral phosphoric acid derivative 728 was used as the organocatalyst to obtain 730 in excellent yields and enantioselectivities …”

Access to 1,2‐Dihydroisoquinolines through Gold‐Catalyzed Formal [4+2] Cycloaddition

“…Based on our previous work on CPA‐catalyzed reactions for the construction of enantioenriched heterocycles,6 we envisioned that the chiral cyclopenta[1,4]diazepine framework could be efficiently constructed through CPA‐catalyzed three‐component tandem reactions of cyclopentane‐1,3‐dione, 1,2‐phenylenediamines, and isatins (Scheme ). Our preliminary investigation on this design, included only one example and the enantioselectivity was poor 3d. Therefore, we wished to extend the study and to carry out a systematic, in‐depth investigation on this designed catalytic asymmetric three‐component reaction as well as to develop an applicable method to construct the enantioenriched cyclopenta[1,4]diazepine framework.…”

New development in the enantioselective synthesis of spiro compounds

“…A similar approach was reported by Liu et al using simple enals 208. The main difference was that his reaction required an oxidant to generate the -enolate (Scheme 118).Scheme 118: Spirocyclization reported by YaoShi et al developed the synthetic procedure for 3,3'spirooxindoles fused with seven-membered rings, based on a 40 tandem reaction 209. Isatin 88, 1,2-diamino benzene 364, and 1,3 diketones 365, catalysed by chiral phosphoric acid LIX, furnished the final spiro compounds 367 in moderate yields…”